Stabilization of G‐Quadruplex DNA with Platinum(II) Schiff Base Complexes: Luminescent Probe and Down‐Regulation of c‐myc Oncogene Expression

Abstract

The interactions of a series of platinum(II) Schiff base complexes with c-myc G-quadruplex DNA were studied. Complex [PtL(1a)] (1 a; H(2)L(1a)=N,N'-bis(salicylidene)-4,5-methoxy-1,2-phenylenediamine) can moderately inhibit c-myc gene promoter activity in a cell-free system through stabilizing the G-quadruplex structure and can inhibit c-myc oncogene expression in cultured cells. The interaction between 1 a and G-quadruplex DNA has been examined by (1)H NMR spectroscopy. By using computer-aided structure-based drug design for hit-to-lead optimization, an in silico G-quadruplex DNA model has been constructed for docking-based virtual screening to develop new platinum(II) Schiff base complexes with improved inhibitory activities. Complex [PtL(3)] (3; H(2)L(3)=N,N'-bis{4-[1-(2-propylpiperidine)oxy]salicylidene}-4,5-methoxy-1,2-phenylenediamine) has been identified with a top score in the virtual screening. This complex was subsequently prepared and experimentally tested in vitro for its ability to stabilize or induce the formation of the c-myc G-quadruplex. The inhibitory activity of 3 (IC(50)=4.4 muM) is tenfold more than that of 1 a. The interaction between 1 a or 3 with c-myc G-quadruplex DNA has been examined by absorption titration, emission titration, molecular modeling, and NMR titration experiments, thus revealing that both 1 a and 3 bind c-myc G-quadruplex DNA through an external end-stacking mode at the 3' terminal face of the G-quadruplex. Such binding of G-quadruplex DNA with 3 is accompanied by up to an eightfold increase in the intensity of photoluminescence at lambda(max)=652 nm. Complex 3 also effectively down-regulated the expression of c-myc in human hepatocarcinoma cells.

A Planar Schiff Base Platinum(II) Complex: Crystal Structure, Cytotoxicity and Interaction with DNA

“…Metal complexes of Schiff bases have been shown to be able to interact with several primary biogenic macromolecules such as DNA, RNA and peptides. [8][9][10] Particularly, the Schiff base metal complexes derived from salicylaldehyde were effective for cleaving DNA. [11][12][13][14] In this paper, we attempt to develop new platinum(II) Schiff base anticancer agents that binding non-covalently to DNA.…”

Structure‐Based Design of Platinum(II) Complexes as c‐myc Oncogene Down‐Regulators and Luminescent Probes for G‐Quadruplex DNA

“…Furthermore, these platinum(II) complexes with p-conjugated aromatic ligands can act as luminescent probes for G-quadruplex DNA due to the photoluminescent properties of transition-metal complexes being sensitive to the local environment. [28][29][30][31] They are non-emissive in aqueous solution due to non-radiative decay of the excited state by complex-solvent interactions, but fluoresce strongly when bound to DNA.…”

Light-induced catalytic and cytotoxic properties of phosphorescent transition metal compounds with a d 8 electronic configuration

“…The photophysical properties of cyclometalated platinum(II) compounds containing tridentate C ∧ N ∧ N ligands (where HC ∧ N ∧ N = 6-phenyl-2,2 -bipyridine or its derivatives), or bidentate C ∧ N ligands (where HC ∧ N = 2-phenylpyridine or its derivatives) have extensively been studied [8]. Their biological properties and applications as turn-on probes for (specific) proteins [37,38], enzyme poisons [39], G-quadruplex DNA stabilizers [40] and PDT agents [29] have recently been reported as well. In a recent study, cyclometalated platinum(II) compounds containing thiophene moiety (figure 16, Pt3 and Pt4) were found to display high emission quantum yields (up to 0.38) and long emission lifetimes (24 μs) [29].…”